The OBJECTIVE of this proposal is to characterize serotonergic (5-HT) projections to forebrain in terms of anatomic and pharmacologic properties that influence cortical function. This project will test the HYPOTHESIS that there are DUAL ASCENDING 5-HT PROJECTIONS which differ in cells of origin, axon morphology, and sensitivity to mood-altering drugs. Anatomic data for two dissimilar 5-HT neuronal systems is supported by evidence that particular psychotropic amphetamines act selectively upon a subset of 5-HT axons, causing 5-HT release followed by terminal degeneration. The present study will (1) analyze the anatomic organization of ascending 5-HT projections, (3) identify the terminal morphology and chemical features of 5-HT axons, and (3) assess regeneration of 5-HT axons after their selective ablation. The AIMS are: 1) to describe the ORIGIN OF 5-HT ORIGIN OF 5-HT PROJECTIONS to selected forebrain areas, and to verify whether the two axon types CONSISTENTLY arise from separate raphe nuclei (DR vs. MR-B9). One class of 5-HT axons will be ablated by neurotoxic amphetamine derivatives; those raphe cells which retain their projections to forebrain will then be located by retrograde axonal transport methods. In addition, to ascertain whether separate raphe nuclei receive different inputs, retrograde transport will be used to identify the source of afferents to each of the midbrain raphe nuclei. 2) Highly-specific antibodies against glutaraldehyde-conjugated 5-HT (and other indoleamines) will be used to detect CHEMICAL DIFFERENCES between raphe neurons. Utilizing these antisera after glutaraldehyde fixation, the morphology of 5-HT SYNAPTIC TERMINALS will be analyzed by confocal and ELECTRON MICROSCOPY. 3) Re- innervation by 5-HT axons will be studied 6-12 months after neurotoxin treatment to identify WHICH RAPHE CELLS UNDERGO SPROUTING, and to determine factors which influence axon regeneration. Quantitative morphometric methods will be used to map retrogradely labeled raphe cell bodies and to measure 50HT axon density. 5-HT projections influence cortical excitability and may be implicated in several neuropsychiatric conditions, particularly dementias and affective disorders. Evidence that many mood- elevating drugs act at 5-HT synapses supports the hypothesis that 5-HT neurons regulate affective state. The identification of dual 5-HT projections that have different chemical and anatomic properties should improve our understanding of the neural mechanisms of mental function and facilitate the treatment of effective and cognitive disorders.